A mechanical tuning mechanism located in the sensory hair cell bundle and intimately associated with the mechano-electric transducer (MET) channels has been described. Termed fast adaptation, this calcium-dependent process has been postulated to underlie in part the cochlea active process, the mechanism responsible for the exquisite sensitivity of the auditory system. Perturbations of this system might result in elevated thresholds, temporary threshold shifts and tinnitus. Understanding the mechanisms responsible for the generation and regulation of adaptation of mechano-electric transduction is therefore critical if the long term goal is to design therapeutic treatments for these maladies. To this end, experiments are designed to quantitatively address several critical issues pertaining to the generation and regulation of the ton topic variations in fast adaptation. The first goal is to determine if intrinsic differences in MET channels exist between high and low frequency cells, specifically focusing on channel kinetics and single channel properties. An interaction between MET channels, probably through summation of intraciliary calcium has been postulated as a mechanism underlying the tontopic differences. Experiments are designed to directly test this hypothesis by coupling multiphoton imaging with electrophysiological recordings. A slower component of adaptation has been described that results in an increase in hair bundle compliance. This slow component may serve to prevent saturation and mechanical damage of the sensory hair bundle. Preliminary data suggests this component may be triggered by an intracellular release of stored calcium, and perhaps operate via a myosin motor, experiments are designed to characterize the mechanisms responsible for generating and the biochemical regulation of this slow form of adaptation. Hair cell calcium channels regulate membrane excitability and dictate transmitter release. Differential regulation of calcium channels based on which function the channels serves may be an important tool for signal processing. Characterization of the biophysical, pharmacological and biochemical properties of these channels is the fourth goal of this project and should yield some exciting new information regarding signal processing.